CN1980695A - 抗原递送载体和构建物 - Google Patents
抗原递送载体和构建物 Download PDFInfo
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- CN1980695A CN1980695A CNA2005800192265A CN200580019226A CN1980695A CN 1980695 A CN1980695 A CN 1980695A CN A2005800192265 A CNA2005800192265 A CN A2005800192265A CN 200580019226 A CN200580019226 A CN 200580019226A CN 1980695 A CN1980695 A CN 1980695A
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Abstract
本发明涉及用于递送抗原到免疫应答靶细胞的碳氟化合物载体。它进一步涉及碳氟化合物载体-抗原构建物以及这种载体与抗原的联合应用,在动物中作为疫苗和免疫疗法。
Description
本发明涉及新的抗原递送构建物和它们在免疫方法中的应用。特别地,本发明涉及在抗人类免疫缺陷型病毒免疫中有用的构建物。
背景技术
我们对哺乳动物免疫应答理解中最近进展已经引导通过预防性接种防止人类中的某些疾病并且通过免疫疗法的使用控制和治疗疾病。可以通过免疫介入处理的疾病的类型包括那些由感染物引起的、癌症、变态反应和自身免疫疾病。在这些情况,最普遍地,医学治疗的前提是抗原到适当的免疫识别细胞的有效递送。例如,预防性接种已经世界性地成功消灭了天花,通过给药携带野生型病毒所有抗原的病毒的活的减弱的株。相似地,在开发了基于来自细菌细胞壁的多糖抗原的疫苗后,由于嗜血杆菌(Haemophilus influenzae)b型流感细菌的感染已经明显地在西方国家减少。而且,一些癌症例如人类黑素瘤对免疫治疗有响应,该治疗使用自体树突细胞(DC)作为细胞佐剂,并且规定从黑素体蛋白gp100衍生的肽作为肿瘤特异性抗原的源以产生细胞介导的免疫应答。
对自身抗原的自身耐受性能通过注射破坏性的免疫应答的靶的特异的神经抗原(neuroantigen)在实验性自身免疫脑脊髓炎的治疗中被恢复。所以,能够通过这样的治疗提供特异性,无需长期的免疫抑制。
对于感染性疾病,发生在疾病控制中最快的进步是针对进入的抗原,抗体能中和感染物或其分泌的毒素,无论这是通过IgM、IgG还是IgA介导的。同样,自身免疫疾病已经用能改善自身抗体行为的抗原治疗。然而,为了消灭病毒感染的细胞、癌症细胞和包含细胞内细菌的细胞,也需要细胞免疫应答。例如,细胞内病毒(例如逆转录病毒、致肿瘤核糖核酸病毒、正粘病毒(orthomyxoviruses)、副黏液病毒、披膜病毒类、杆状病毒、沙粒病毒、腺病毒、疱疹病毒、痘病毒、乳多泡病毒和风疹病毒)能复制并传播到相邻的细胞而不会暴露于抗体。细胞介导的免疫的重要性由于具有初级T-细胞缺陷的儿童不能清除这些病毒而着重,而具有免疫球蛋白缺陷但具有完整的细胞介导的免疫的病人不遭受这样的障碍。少量的但是重要的细菌、真菌、原生动物和寄生虫在宿主细胞中生存并复制。这些有机体包括分枝杆菌(结核和麻风病)、军团杆菌(军团病(Legionnaires Disease))、立克次氏体(落基山斑疹热(Rocky Mountain spotted fever))、衣原体、单核细胞增多性李司忒氏菌(Listeria monocytogenes)、布鲁氏菌、弓形体(Toxoplasmagondii)、利什曼原虫、锥虫、白色念珠菌(Candida albicans)、隐球菌、红酵母和肺囊虫。通过生存在细胞内部,这些有机体不被循环的抗体接触。天然免疫应答也是无效的。主要的抗这些有机体的免疫防御是细胞介导的免疫;包括两种CD8+溶细胞的T淋巴细胞和CD4辅助T淋巴细胞。
能引起有效的和持续的细胞介导的免疫应答的疫苗和免疫疗法的开发依然是疫苗学(vaccinology)中最大的挑战之一。特别地,用于预防和治疗人类免疫缺陷型病毒(HIV)感染的安全和有效的疫苗的开发被候选疫苗不能刺激强的、持久的和疾病相关的细胞免疫所妨碍。
负责消灭细胞内病原体或癌症细胞的宿主细胞介导的免疫应答被称为Th1应答。其特征在于诱导细胞毒素的T-淋巴细胞(CTL)和T-辅助淋巴细胞(HTL),引起免疫效应机制以及免疫刺激细胞因子例如IFN-γ和IL-2的活化。Th1应答在控制病毒感染中的重要作用最近被Lu等人显示(NatureMedicine(2004))。这个有慢性HIV-1感染的个体的临床研究显示病毒负荷的抑制与表达HIV-1-特异的IL-2或IFN-γ的CD4+T细胞和特异HIV-1的CD8+效应细胞的应答都有正相关。目前通过疫苗和免疫疗法促进细胞免疫的免疫学战略包括病原体活的减弱版的开发和活载体的应用以递送合适抗原或编码这样抗原的DNA。这些进展被越来越严格的制度环境中的安全考虑限制。而且,由生产方法的规模可伸缩性和成本引起的问题经常限制生物起源的产品的商业竞争力。
在本上下文中,基于肽使用的合理规定的合成疫苗已受到相当的注意,作为开发新的预防性疫苗和免疫疗法的潜在候选。T细胞和B细胞的表位(epitope)代表免疫原的唯一活性部分,其被适应性免疫系统识别。覆盖T或B细胞表位区域的小肽能被用作免疫原以诱导免疫应答,其最终与该序列所来自的天然抗原交叉反应。肽是非常吸引人的抗原,因为它们被很好地化学限定、高度稳定并且能被设计包含T和B细胞表位。T细胞表位,包括CTL和T辅助细胞的表位,能基于它们结合MHC分子的能力而被选择,以这样的方式能获得大的群体范围(The HLA Factsbook,Marsh,S.,Academic Press.2000)。而且,选择合适的T和B细胞表位的能力使免疫应答直接针对病原体的多个保守表位,其以高度序列变化为特征(例如HIV、丙型肝炎病毒(HCV)、和疟疾)。
为了刺激T淋巴细胞应答,包含在疫苗或免疫治疗产物中的合成的肽优选地应该被抗原递呈细胞并且特别是树突细胞内化。树突细胞(DC)在T细胞介导的初次免疫应答的引发中起重要作用。这些细胞在成熟中的两个阶段与不同功能相关。幼树突细胞(iDC)位于多数组织或循环系统中并且被召集到炎症部位。它们是高度特化的抗原捕捉细胞,表达大量受体参与抗原摄入和吞噬。抗原捕捉和处理后,iDC移到淋巴结或脾中本地T细胞位置。在此过程中,DC失去它们的抗原捕捉能力变成免疫刺激成熟DC(mDC)。
树突细胞是有效的递呈细胞,启动宿主对与I类和II类MHC分子关联的肽抗原的免疫应答。它们能刺激原初的CD4和CD8 T细胞。根据目前抗原处理和递呈路径的模型,外源抗原被内化进入抗原递呈细胞的细胞内分隔的区域,在那它们被降解为肽,其中一些结合MHC的II类分子。然后成熟的II类MHC/肽复合物被传输到细胞表面呈递给CD4 T-淋巴细胞。相反,内源抗原在被输送到细胞质结合新的I类MHC分子之前在细胞质中被蛋白体(proteosome)的作用降解。与肽复合的稳定的I类MHC分子然后被运输到细胞表面刺激CD8 CTL。外源抗原在称作交叉呈递的过程中通过专职的APC也能被呈递给I类MHC分子。包含细胞外抗原的吞噬体(Phagosome)可与内质网融合,抗原可能获得将肽加载到I类MHC分子必需的机械。这是很认知的,然而,自由肽自己经常是弱的免疫原(FieldsVirology,Volume l,Third Edition,1996)。
为了优化肽疫苗或疗法的效力,多种疫苗战略被开发,引导抗原进入抗原呈递细胞以靶向I类MHC路径并引起细胞毒性的T-淋巴细胞(CTL)应答。作为合成递送系统的例子,脂肪酰链被共价连接到肽作为递送表位进入I类MHC细胞内区域的方法以诱导CTL的活性。这样的脂肽,例如在美国专利5,871,746中描述了单十六酰链连接代表来自HIV Env蛋白的表位的肽。其它技术也被提供以将表位递送进入细胞内区域并因而诱导CTL。这些包括例如Penetratin、TAT和它的衍生物的载体、DNA、病毒载体、病毒小体(virosome)和脂质体(liposome)。然而,这些系统或者引起很弱的CTL应答、有相联系的毒性问题或是复杂的并且以商业规模制造是昂贵的。
因此,认识到需要在疫苗和药物的开发中改进载体以引导抗原的细胞内递送,意在引起细胞免疫应答。免疫疗法或疫苗内容中的载体是任何能在宿主中输送或引导抗原到达免疫应答细胞的媒介物。氟化的表面活性剂已显示与它们相应的氢化物相比有更低的临界胶束浓度,并且因此与相当的碳氢分子相比在更低的浓度自我组织成为胶束结构。这样的物理化学性质与氟化链联系的强疏水相互作用和低范德华(Van der Waal’s)相互作用有关,其显著增加氟化两亲物在水中自我装配和在界面聚集的趋势。这样的大分子结构的形成促进它们通过例如抗原呈递细胞等细胞的细胞内摄入(Reichel F.等人.J.Am.Chem.Soc.1999,121,7989-7997)。此外,溶血活性被很大地降低并且当氟化链被引入表面活性剂时经常被抑制(Riess,J.G.;Pace,S.;Zarif,L. Adv.Mater.1991,3,249-251)因此引起细胞毒性的降低。
本发明试图通过使用新的碳氟化合物载体以增加进入的抗原的免疫原性,克服递送抗原到免疫应答细胞的问题。碳氟化合物载体可包括一种或多种从全碳氟化合物(perfluorocarbon)衍生的链或混合的碳氟/烃基,并且可以是饱和或不饱和的,每条链有从3到30个碳原子。为通过共价键连接载体和抗原,反应基团或配基被掺入作为载体的组分,例如包括-CO-、-NH-、S、O或任何合适的基团;应用这样的配基以获得共价键是本技术领域非常已知的。反应基团可位于碳氟化合物分子的任何位置。碳氟化合物载体与抗原的偶联可通过功能基团获得,所述功能基团例如-OH、-SH、-COOH、-NH2天然具有或在抗原的任何位点引入。这样的键的例子包括酰胺键、腙键(hydrazone)、二硫键、硫醚键和肟(oxime)键。替代地,非共价键能被使用,例如可通过连接肽抗原的组氨酸残基和碳氟化合物载体上羧酸到一起的阳离子形成离子相互作用。可选择地,间隔单元(space element)(肽或非肽)可被掺入以允许从碳氟化合物单元切割抗原,以在抗原递呈细胞内部处理并优化抗原的空间递呈。间隔物也可被掺入以协助分子的合成并改进它的稳定性和/或溶解性。间隔物的例子包括聚乙二醇(PEG)、例如赖氨酸或精氨酸的可被蛋白裂解酶裂解的氨基酸和碳氢化合物。
因此,在第一方面,本发明提供有化学结构CmFn-CyHx-L的碳氟化合物载体或其衍生物,其中m=3到30,n<=2m+1,y=0到15,x<=2y,(m+y)=3-30以及L是有助于与抗原共价附着的配基。
在本发明的上下文中“衍生物”指碳氟化合物相对小的修饰,如此化合物仍然能如在此描述递送抗原。因此,例如,多个氟部份能用其它卤素部份替换例如Cl、Br或I。另外可能用甲基基团替代多个氟部份并且仍然保持如此描述的分子的性质。
在上述公式的一具体的实施方案中,载体可以是下述公式(I)的全氟十一烷酸(perfluoroundecanoic acid):
或替代地下述公式(II)的2H,2H,3H,3H-全氟十一烷酸:
或下述公式(III)的十七氟十五酸(heptadecafluoro-pentadecanoic acid):
在本发明的第二方面提供了载体-抗原构建物CmFn-CyHx-(Sp)-R,其中Sp是任选的化学间隔物部份以及R是抗原。
与载体连接的抗体可以是任何能够在包括人类的动物中诱导免疫应答的抗原。优选地免疫应答在宿主内有有益的作用。抗原可以从病毒、细菌或分枝杆菌、寄生虫、真菌、或任何感染物或自体抗原或过敏原衍生。
病毒的例子包括但不限于人类免疫缺陷型病毒-1(HIV-1)或人类免疫缺陷型病毒-2、流感病毒、疱疹病毒HSV-1和HSV-2、甲型肝炎病毒(HAV)、乙型肝炎病毒(HBV)、或丙型肝炎病毒(HCV)。
细菌和分枝杆菌的例子包括但不限于结核分枝杆菌、军团杆菌、立克次氏体、衣原体、和单核细胞增多性李司忒氏菌(Listeria monocytogenes)。
寄生虫的例子包括但不限于恶性疟原虫(Plasmodium falciparum)和其它疟原虫家族的种类。
真菌的例子包括但不限于白色念珠菌(Candida albicans)、隐球菌、红酵母和肺囊虫。
自体的或自身的抗原包括但不限于以下与癌症相关的抗原,在乳腺癌中表达的HER-2/neu、在黑素瘤中表达的gp100或MAGE-3,在结肠直肠癌中表达的P53、以及在多种人类癌症中表达的NY-ESO-1或LAGE-1。
过敏原包括但不限于与对蜜蜂严重反应相关的磷脂酶A2(API ml),与对屋尘螨(Dermatophagoides pteronyssinus)反应相关的Derp-2、Der p 2、Derf、Der p 5和Der p 7,蟑螂过敏原BIa g 2以及主要桦树花粉过敏原Bet v 1。
因此在实施方案中,本发明提供载体-抗原构建物,其中抗原是或代表来自病毒、细菌、分枝杆菌、寄生虫、真菌、自体的蛋白或过敏原的抗原。
抗原可以是蛋白质、蛋白亚基、肽、碳水化合物、脂或其组合,只要它们呈递免疫学可识别的表位。这样的抗原可以通过从天然蛋白纯化衍生或通过重组技术或通过化学合成生产。抗原制备的方法在本技术领域是很已知的。此外抗原也包括编码抗原的肽或蛋白的DNA或寡核苷酸。
因此仍然在进一步的实施方案中,本发明提供载体-抗原构建物,其中抗原是蛋白质、蛋白亚基、肽、碳水化合物或脂或其组合。
为了构建物是免疫学活性的,抗原必须包括一个或多个表位。用于本发明的肽或蛋白优选地包括至少7个,更优选地在9和100个氨基酸之间并且最优选地在大约15到35个氨基酸之间的序列。优选地,带有表位的氨基酸序列的肽被选择以增加分子在水性溶剂中的溶解性。此外,不与载体轭合的肽的末端可以变化以促进构建物的溶解性,通过形成例如微团、薄层、小管或脂质体的多分子结构。例如,带正电荷的氨基酸能被加到肽以促进微团的自发装配。肽的或者N末端或者C末端能被偶联到载体以创造构建物。为有助于大量合成构建物,能修饰肽的N或C末端氨基酸残基。当期望的肽对肽酶的切割特别敏感时,通常肽键能被不可切割的肽模拟物代替,这样的键和合成方法在本技术领域是很已知的。
作为特殊的例子,代表来自HIV-1的Env(301-322)蛋白的表位的肽NNTRKRIRIQRGPGRAFVTIGK-NH2,其显示是免疫学活性的。仍然这代表本发明的另一个实施方案(参见http://www.hiv.lanl.gov/content/immunology/index.html)。
在附加到配基之前一个以上的抗原可连接在一起。一个这样的例子是使用融合肽,其中随机的T辅助细胞表位能与一个或多个CTL表位或一个或多个B细胞表位共价连接,其中所述B细胞表位能是肽、碳水化合物或核酸。作为例子,随机的T辅助细胞表位能够是PADRE肽、破伤风类毒素肽(830-843)或流感血细胞凝集素HA(307-319)。
因此在另一个实施方案中,载体-抗原构建物的R是连接在一起的不只一个的表位或抗原。表位也可以是线性重叠,因此创造密集排列的多特异性表位的簇。
由于碳氟化合物特征性的强非共价分子相互作用,抗原也可以与载体非共价地联合并且仍然获得通过抗原呈递细胞顺利摄取的目的。
本发明也提供疫苗和免疫疗法,其包括一种或多种碳氟化合物载体-抗原构建物。期望这类的多成分产物,因为它们可能更有效地引起合适的免疫应答。例如,HIV免疫治疗的最佳制剂可包括来自不同HIV蛋白的多个表位。在此情况,每个表位可连接共同的碳氟化合物载体,或者每个表位能结合专门的载体。替代地,多样表位可被掺入制剂以给予针对一种范围病原的免疫性。多成分产物可包括一个或多个载体-抗原构建物,更优选地2到大约20个,更优选地3到大约8个。
本发明的组合物包括碳氟化合物载体,其联系抗原,任选地与一种或多种药物学可接受传递体和/或佐剂在一起。这样的佐剂,能进一步使免疫应答可能发生,可包括但不限于胞壁酰二肽(MDP)衍生物、CpG、单磷酰类脂A、水包油佐剂、油包水佐剂、铝盐、细胞因子、免疫刺激复合体(ISCOM)、脂质体、微粒、皂苷、细胞因子、或细菌毒素以及类毒素。其它有用的佐剂对本领域的技术人员是很已知的。如果需要,传递体的选择常常是组合物递送路径的功能。在本发明中,组合物可配制成用于给药的任何合适路径和方法。药物学可接受传递体或稀释剂包括那些在适合口、眼、直肠、鼻、局部的(包括口腔的和舌下的)、阴道的或胃肠外的(包括皮下的、肌内的、静脉的、真皮内的)给药制剂中使用的。
制剂可以任何合适的形式给药,例如液体、固体、气溶胶或气体。例如口服制剂可采取乳剂、糖浆剂或溶液或片剂或胶囊的形式,其可被包覆肠衣以防止活性组分在胃中被降解。鼻制剂可以是喷雾剂或溶液。透皮制剂可适于它们特别的递送系统并且可包括贴片。注射制剂可以是溶液或是在蒸馏水或其它药物学可接受溶剂或悬浮剂中的悬液。
因此在进一步方面,本发明提供预防或治疗制剂,其包括载体-抗原构建物,带有或没有适当的传递体和/或佐剂。
对病人给药疫苗或免疫疗法的合适剂量会在临床中确定。然而作为指导,适当的人类剂量可从1到1000μg,其根据优选的给药路径。多种剂量可被需要以获得免疫学作用,其如果需要,会典型地间隔2到12周之间给药。当需要在更长时期后加强免疫应答,可应用间隔3个月到5年的重复剂量。
制剂可将载体-抗原构建物与其它活性成分联合以使一个以上的疫苗或药物的给药起作用。通过2个或更多活性剂的共给药也可能观察到协同作用。在治疗HIV感染中,这样的药物的例子是高效抗反转录病毒疗法(Highly Active Anti-Retroviral Therapy(HAART))。
在其它方面,本发明提供:
i)免疫原构建物的应用,如在此描述的,在制备为治疗或防止疾病或其症状的药剂中的应用。
ii)治疗的方法,通过在给药在此描述的构建物或制剂之后诱导免疫应答;
iii)碳氟化合物载体和碳氟化合物载体-抗原构建物在医学中的应用。
实施例引用的图,其中:
图1:显示多种肽和构建物在T=0的HPLC色谱;
图2:显示多种肽和构建物在40℃保存27天的HPLC色谱;
图3:显示2个肽FAVS-3-ENV和FAVS-1-ENV的临界微团浓度评价;
图4:显示不同的肽构建物放置20小时后通过准光散射(quasi lightscattering)光谱测定仪的粒度分析;
图5:显示单次免疫(A,B)、第一次加强(C,D)和第二次加强(E,F)后,通过小鼠体外IFN-γ ELISPOT分析评定的细胞免疫应答;
图6:显示在体内由不同碳氟化合物-肽构建物起动的T淋巴细胞的性质;
图7:显示3次单独用FAVS-1-ENV或与莫拉丁酯(murabutide)联合免疫后,通过小鼠体外IFN-g ELISPOT分析评定的细胞免疫应答;
图8:显示3次单独用FAVS-1-ENV或与莫拉丁酯联合注射后细胞因子的测量;以及
图9:显示2次单独用FAVS-1-ENV或与莫拉丁酯(murabutide)联合鼻内给药后,通过小鼠体外IFN-g ELISPOT分析评定的细胞免疫应答。
实施例1
碳氟化合物-载体化肽的合成
下述的碳氟化合物-载体肽被合成:
FAVS-1-ENV:NNTRKRIRIQRGPGRAFVTIGK-C8F17(CH2)2CO-K-NH2
FAVS-2-ENV:NNTRKRIRIQRGPGRAFVTIGK-C8F17(CH2)6CO-K-NH2
FAVS-3-ENV:IRIQRGPGRAFVTIGKK-CO(CH2)2-(PEG)4-C8F17(CH2)6CO-K-NH2
其中标准氨基酸的单字母代码被使用,并且PEG是CH2-CH2-O。
NNTRKRIRIQRGPGRAFVTIGK是人类免疫缺陷型病毒(HumanImmunodeficiency Virus)的ENV(301-322)肽。
肽的合成在ABI 430或ABI 433自动肽合成仪上进行,在Rink酰胺树脂(加载0.38mmol/g)上使用Nsc(2-(4-硝基苯磺酰)乙氧羰基)或Fmoc((9-芴甲氧羰基)氨基酸。偶联用HOCt(6-氯-氧苯并三唑)和DIC(1,3-二异丙基碳二亚胺)促进,并且在DMF(二甲基甲酰胺)中使用20%哌啶进行Fmoc/Nsc脱保护。作为每个循环的部分未偶联的N末端用乙酸酐加帽。使用TFA、水和TIS(二异丙基硅烷)(95∶3∶2)获得从树脂切割肽以及相伴侧链的脱保护,产物的粗分离物被沉淀进入冷却的二乙基醚。通过制备HPLC进行纯化,使用Jupiter C5或Luna C18(2)柱(250×22mm),并且肽的质量通过质谱仪证实。
在进行实验前验证肽的纯度,通过HPLC(HP 1050)在梯度洗脱下使用来自Supelco的柱(C5,250×4.6mm,300A,5μm)。溶剂A(90%水、10%乙腈、0.1%TFA),溶剂B(10%水、90%乙腈、0.1%TFA)。30分钟内使用B的0到100%的梯度并且柱温度是40℃。UV检测器的波长设在215nm。在各情况碳氟化合物-载体肽的纯度大于90%。
包含冻干的载体-肽的密封的样品的化学稳定性被在4℃、20℃和40℃与作为参照物(NNTRKRIRIQRGPGRAFVTIGK-NH2)的未载体化的肽一起被评定。对于时间的稳定性被用上述的条件通过HPLC检测。数据显示在图1和2中。
对于每个肽轭合物,在40℃孵育27天后没有观察到降解的迹象,如在T=0发现的,有单峰在相同的滞留时间洗脱。
实施例2
碳氟化合物-载体化肽的物理化学分析
(i)溶解性
碳氟化合物-载体肽在水溶液中的对药学制剂有用的浓度的溶解性被确定。通过用PBS(0.01M,pH7.2)在一个浓度范围内溶解冻干的肽粉,在20℃制备肽的溶液。制品然后涡旋1分钟。整分部分被收集并且溶液的其余部分在12,000rpm离心10分钟。向包含25μl整分部分的每种肽的系列稀释物的平底96孔板加入200μl BCA工作反应物(Pierce,UK),其包括溶液A(4,4’-二羧酸-2,2’二喹啉(bicichoninic acid)、碳酸钠、酒石酸钠溶于氢氧化钠0.1M溶液,50体积.)和B(4%硫酸铜溶液,1体积)。在37℃孵育45分钟并且冷却10分钟,在570nm测量吸光度。板用Wallac Victor多标记检测仪(multilabel counter)(Perkin Elmer)分析。对每种肽,标绘和使用校准曲线以确定在溶液部分肽的浓度,表示为nmol/ml。数据显示在表1。在用于小鼠免疫研究使用的抗体浓度,发现所有的肽是完全溶解的。
表1:通过蛋白分析方法进行的溶解性分析的总结
(ii)临界微团浓度[CMC]
通过结合8-苯胺基-1-萘-硫酸(ANS)的染料确定碳氟化合物-载体化的肽在生理磷酸缓冲液中的临界微团浓度。从肽300μg/ml的溶液开始,在20℃于PBS(0.01M,pH7.2)2倍系列稀释的肽和肽载体的溶液中制备,从其中取出200μl加入微量培养板的孔中。40μl在PBS中新鲜溶解的ANS然后被加入每个孔。2分钟后培养板在355nm被激发并且在460nm在Victor微量培养板荧光光度计上扫描。以线性刻度对于对数刻度的浓度上绘制比例(样品的荧光密度/空白的荧光密度)。数据显示在图3。
(iii)粒度分析
粒度分析在Malvem 4700C准光散射(quasi light scattering)光谱测定仪(Malvem Ltd,UK)上进行,装备了调节在488nm的氩激光(Uniphase Corp.,San Jose,CA)。样品维持在25℃的温度。激光有可变的检测器几何位置用于角度依赖的测量。测量在90°和60°的角度进行。溶液是通过溶解肽于滤过的0.01M磷酸盐缓冲液到500nmol/ml的浓度并且涡旋1分钟制备的。然后溶液分配到试管中(1ml的工作体积)。测量在15分钟后以90°的角度进行(图4)。Kcount值的输出与检测的颗粒数量成比例;在所有情况,Kcount>10以保证获得可靠的大小分布测量。
表2:在PBS中微团溶液的粒度
实施例3
(i)碳氟化合物-载体化的肽的免疫原性
无特异病原体的小鼠(6-8周雌性Balb/c)购自Harlan(UK)。肽ENV、FAVS-1-ENV、FAVS-2-ENV或FAVS-3-ENV溶于PBS(0.01M,pH7.2)。基于从氨基酸分析获得的净肽含量,每个剂量标准化到肽50nmol/ml。小鼠(每组3只)用100μl体积的pH7.2的PBS中的50nmol肽在肩胛间区域的皮下进行皮下免疫。在10天的间隔给药3个剂量。小鼠组接受自由肽与Complete Freund′s佐剂混合的起始剂量(PBS中的50nmol肽用等体积的佐剂乳化),并且Incomplete Freund′s佐剂的增强剂量作为阳性对照。末次免疫后10天,小鼠被处死并且脾被移去以评估对肽的细胞免疫应答。为确定免疫应答发展的过程,也建立了接受单个和两个剂量肽的小鼠组。
通过载体化肽起始的体内细胞应答通过在新鲜脾细胞上的IFN-γELISPOT检测,以计算免疫后体外肽特异性产生IFN-γ的细胞并且更特异地起始的肽特异性的CD8+T淋巴细胞的数量。脾细胞体外用包括很已知的T辅助细胞表位的ENV(301-322)NNTRKRIRIQRGPGRAFVTIGK肽和相应于CD8表位(I类MHC H-2Dd-限定的,称作P18-I10)的短肽ENV(311-320)RGPGRAFVTI再刺激,以覆盖细胞免疫应答的两种成分(T辅助细胞和CD8 T细胞活性)。
收集每组小鼠的脾并且分离脾细胞。计数前细胞被在RPMI-1640中洗3次。根据生产商的说明并依据以下的修饰使用Diaclone Kit(Diaclone,France),进行小鼠IFN-g Elispot分析。在18小时的过程中、在37℃、5%CO2环境下,以5×105/孔的细胞密度培养的2份脾细胞被分散在抗IFN-γ抗体包被的以PVDF为底的孔(96孔multiscreenTM-IP微量培养板-Millipore),其中培养液中(RPMI-1640)有合适浓度的肽(10、1、0mg/ml的T辅助细胞的ENV(301-322)或P18-I10 CTL表位)、5μMβ-巯基乙醇、5mM谷氨酰胺并添加10%胎牛血清。使用Carl Zeiss Vision ELIspot阅读器设备计数点。结果对应于每个条件获得的平均值减去背景。结果表示为点形成单位(spot forming units)(SFC)/106输入的脾细胞(图5)。
(ii)体内通过碳氟化合物-肽起始的T淋巴细胞的性质(CD4和CD8 T细胞的分离)
来自免疫的小鼠的脾细胞以细胞密度2.5×106/孔分散在48孔微量培养板,并伴有1μg/ml的T辅助细胞ENV(301-322)或P18-I10 CTL肽。在第3天,5ng/ml的重组小鼠IL-2被加入每个孔。在第7天,预刺激的脾细胞被收集,在RPMI 1640中洗3次、计数以及根据生产商的说明使用轭合单克隆大鼠抗小鼠CD8a和CD4抗体的磁性珠子(MACS,Microbeads MiltenyiBiotec,UK)通过磁性细胞拣选(magnetic cell sorting)而分离。在12小时的过程中、在37℃、5%CO2环境下,CD4和CD8+T细胞以2.5×105/孔的细胞密度以2份被分散在抗体包被的以PVDF为底的孔(96孔multiscreenTM-IP微量培养板-Millipore),其中培养液中(RPMI-1640)有1mg/ml的肽、5μMβ-巯基乙醇、谷氨酰胺、非基本氨基酸、丙酮酸钠并添加10%胎牛血清。使用Carl Zeiss Vision ELIspot阅读器设备计数点。结果对应于每个条件获得的平均值减去背景(<10点)。结果表示为点形成单位(SFC)/106输入的脾细胞。
根据体外IFN-γELISPOT分析,在体内单次暴露于抗原后,FAVS-肽构建物能起始对长(ENV301-322)和短ENV肽(P18-I10 CTL表位)的强的细胞免疫应答(图5A和B)。图6显示CD4+和CD8+ENV-特异性T细胞都有效地在体内被起始。
用FAVS-肽起始后的应答的强度与用在Freund′s佐剂中乳化的天然肽免疫的小鼠获得的应答在相同的范围。ENV-特异性T细胞应答在第一次和第二次用FAVS-1-ENV制剂(图5C、D、E、F)加强后清楚地被放大,如图6总结的。
这清楚地显示FAVS-肽在体内能被抗原递呈细胞摄取以到达I类MHC和II类MHC路径并且因此起始强的细胞免疫应答。
实施例4
碳氟化合物-载体化肽与合成的佐剂共给药的免疫原性
为了评价合成的免疫促进剂对FAVS-肽定量和定性免疫原性的潜在影响,FAVS-1-ENV被单独注射并且与莫拉丁酯联合。莫拉丁酯(N-乙酰-胞壁酰-L-丙氨酰-D-谷氨酰胺-O-正丁酰-酯;胞壁酰二肽和NOD-2促效剂的合成衍生物)是合成的免疫增强剂,能活化天然免疫机制并且已知当与免疫原联合时提高细胞和激素应答(″Immune and antiviral effects of the syntheticimmunomodulator murabutide:Molecular basis and clinical potential″,G.Bahr,in:″Vaccine adjuvants:Immunological and Clinical Principles″,eds Hacket和Ham(2004),Humana Press)。
无特异病原体小鼠(6-8周雌性Balb/c)购自Harlan(UK)。FAVS-1-ENV构建物以2个不同剂量使用,一组小鼠接受50nmole和第二组接受5nmole的构建物。小鼠(每组3只)在肩胛间区域的皮下或者单独用FAVS-1-ENV或者与100μg的莫拉丁酯联合在总体积100μl的pH7.2的PBS中进行皮下免疫。在10天的间隔给药3个剂量。也建立只接受莫拉丁酯的对照组。
末次免疫后10天,小鼠被处死并且脾被移去以评价对T辅助细胞ENV(301-322)或P18-I10 CTL表位肽的细胞免疫应答。干扰素-γElispot以及Th-1和Th-2细胞因子检测如实施例3中描述的在分离的脾上进行。简言之,在18小时的过程中、在37℃、5%CO2环境下,脾细胞培养在有合适浓度肽(10或0μg/ml的T辅助细胞ENV(301-322)或P18-I10 CTL表位)的培养液中。然后进行IFN-g Elispot分析。用Carl Zeiss Vision Elispot阅读器设备计数点。结果对应于每个条件获得的平均值减去背景(<10点)。结果表示为点形成单位(SFC)/106输入的脾细胞(图7)。
多种细胞因子(IL-2、IFN-g、IL4、IL5、IL-10、IL-13)检测在用5nmol剂量FAVS-1-ENV免疫的小鼠的用ENV(301-322)肽再刺激的新鲜脾细胞上进行。上清液在24小时和48小时被收集。细胞培养上清样品中的细胞因子(IL-2、IL4、IL5、IL10、IL-13、IFN-γ)水平根据SearchLightTM ProteomicArrays(Pierce Biotechnology,Wobum,MA)开发的多重形式(mutiplex format)用细胞因子特异性夹心(Cytokine specific Sandwich)ELISA测定。结果以细胞因子pg/ml表示。
只给药FAVS-1-ENV显示主要诱导Th-1细胞因子(即IL-2和IFN-g)的产生,Th-2细胞因子也有低量的产生。制剂中包括莫拉丁酯引起诱导更平衡的Th-1/Th-2应答伴有更高的Th-2细胞因子水平例如IL-5、IL-10和IL-13(图8)。
实施例5
粘膜给药的碳氟化合物-载体化的肽的免疫原性
无特异病原体小鼠(6-8周雌性Balb/c)购自Harlan(UK)。
两次鼻内给药FAVS-1-ENV(50nmole/小鼠),只在0.01M PBS中或与100μg莫拉丁酯联合,两次给药间隔10天。小鼠用异氟烷(Isoflo,Solvay,UK)轻微麻醉。用微量加液器给药20μl可溶性肽溶液(10μl/鼻孔)。对照组只接受PBS。每个剂量组包括6只动物。小鼠在末次给药后10天用二氧化碳窒息处死。每组小鼠的脾被移去、收集并且脾细胞被分离。计数前细胞用RPMI-1640洗3次。使用Thomas计数玻片计数。在18小时的过程中、在37℃、5%CO2环境下,来自单个小鼠的脾细胞用合适浓度的肽(10或0μg/ml的T辅助细胞ENV(301-322)或P18-I10 CTL表位)在培养液中培养。然后如在实施例3中描述的使用Diaclone Kit进行IFN-g Elispot分析。用Carl Zeiss Vision Elispot阅读器设备计数点。结果对应于每个条件获得的平均值减去背景(<10点)。结果表示为点形成单位(SFC)/106输入的脾细胞。数据代表6只小鼠的平均值。
或者单独用FAVS-1-ENV或者与莫拉丁酯联合进行鼻内免疫的每组所有6只小鼠产生强的全身T细胞应答。与莫拉丁酯联合引起产生IFN-γ的T细胞数量的适度增加(图9)。
实施例6
举例说明HIV肽
连接到碳氟化合物载体以产生用于HIV预防或治疗的疫苗的候选肽可能包括以下一种或多种肽或其片段、或类似物(包括来自HIV-1相应的共有序列、祖先序列或中央树(central tree)序列的序列,其代表不同进化枝(clade)例如但不限于进化枝A、B、C、D、F、G和H,如参见2004 Los Alamos NationalLaboratory数据库)或其天然或非天然的变异体,但不必只限于此。使用标准的单字母和3字母的氨基酸编码。与参照序列相比类似物有至少50%的相同。优选地类似物对于天然发生的序列有80、85、90、95、98或99%的相同。以下提供的序列长度为35个氨基酸。包括一个或多个表位的这些序列的片段也是用于连接到碳氟化合物载体的候选肽。
SEQID No1
WKGEGAVVIQDNSDIKVVPRRKAKIIRDYGKQMAG
Trp-Lys-Gly-Glu-Gly-Ala-Val-Val-Ile-Gln-Asp-Asn-Ser-Asp-Ile-Lys-Val-Val-Pro-Arg-Arg-Lys-Ala-Lys-Ile-Ile-Arg-Asp-Tyr-Gly-Lys-Gln-Met-Ala-Gly
SEQ ID No2
EIYKRWIILGLNKIVRMYSPTSILDIRQGPKEPFR
Glu-Ile-Tyr-Lys-Arg-Trp-Ile-Ile-Leu-Gly-Leu-Asn-Lys-Ile-Val-Arg-Met-Tyr-Ser-Pro-Thr-Ser-Ile-Leu-Asp-Ile-Arg-Gln-Gly-Pro-Lys-Glu-pro-Phe-Arg
SEQ ID No3
EHLKTAVQMAVFIHNFKRKGGIGGYSAGERIVDII
Glu-His-Leu-Lys-Thr-Ala-Val-Gln-Met-Ala-Val-Phe-Ile-His-Asn-Phe-Lys-Arg-Lys-Gly-Gly-Ile-Gly-Gly-Tyr-Ser-Ala-Gly-Glu-Arg-Ile-Val-Asp-Ile-Ile
SEQ ID No4
WEFVNTPPLVKLWYQLEKEPIVGAETFYVDGAANR
Trp-Glu-Phe-Val-Asn-Thr-pro-pro-Leu-Val-Lys-Leu-Trp-Tyr-Gln-Leu-Glu-Lys-Glu-Pro-Ile-Val-Gly-Ala-Glu-Thr-Phe-Tyr-Val-Asp-Gly-Ala-Ala-Asn-Arg
SEQ ID No5
GERIVDIIATDIQTKELQKQITKIQNFRVYYRDSR
Gly-Glu-Arg-Ile-Val-Asp-Ile-Ile-Ala-Thr-Asp-Ile-Gln-Thr-Lys-Glu-Leu-Gln-Lys-Gln-Ile-Thr-Lys-Ile-Gln-Asn-Phe-Arg-Val-Tyr-Tyr-Arg-Asp-Ser-Arg
SEQ ID No6
FRKYTAFTIPSINNETPGIRYQYNVLPQGWKGSPA
Phe-Arg-Lys-Tyr-Thr-Ala-Phe-Thr-Ile-Pro-Ser-Ile-Asn-Asn-Glu-Thr-Pro-Gly-Ile-Arg-Tyr-Gln-Tyr-Asn-Val-Leu-pro-Gln-Gly-Trp-Lys-Gly-Ser-Pro-Ala
SEQ ID No7
NWFDITNWLWYIKIFIMIVGGLIGLRIVFAVLSIV
Asn-Trp-Phe-Asp-Ile-Thr-Asn-Trp-Leu-Trp-Tyr-Ile-Lys-Ile-Phe-Ile-Met-Ile-Val-Gly-Gly-Leu-Ile-Gly-Leu-Arg-Ile-Val-Phe-Ala-Val-Leu-Ser-Ile-Val
SEQ ID No8
ENPYNTPVFAIKKKDSTKWRKLVDFRELNKRTQDF
Glu-Asn-Pro-Tyr-Asn-Thr-Pro-Val-Phe-Ala-Ile-Lys-Lys-Lys-Asp-Ser-Thr-Lys-Trp-Arg-Lys-Leu-Val-Asp-Phe-Arg-Glu-Leu-Asn-Lys-Arg-Thr-Gln-Asp-Phe
SEQ ID No9
VASGYIEAEVIPAETGQETAYFLLKLAGRWPVKTI
Val-Ala-Ser-Gly-Tyr-Ile-Glu-Ala-Glu-Val-Ile-Pro-Ala-Glu-Thr-Gly-Gln-Glu-Thr-Ala-Tyr-Phe-Leu-Leu-Lys-Leu-Ala-Gly-Arg-Trp-Pro-Val-Lys-Thr-Ile
SEQ ID Nol0
PDKSESELVSQIIEQLIKKEKVYLAWVPAHKGIGG
Pro-Asp-Lys-Ser-Glu-Ser-Glu-Leu-Val-Ser-Gln-Ile-Ile-Glu-Gln-Leu-Ile-Lys-Lys-Glu-Lys-Val-Tyr-Leu-Ala-Trp-Val-Pro-Ala-His-Lys-Gly-Ile-Gly-Gly
SEQ ID No11
NRWQVMIVWQVDRMRIRTWKSLVKHHMYISRKAKG
Asn-Arg-Trp-Gln-Val-Met-Ile-Val-Trp-Gln-Val-Asp-Arg-Met-Arg-Ile-Arg-Thr-Trp-Lys-Ser-Leu-Val-Lys-His-His-Met-Tyr-Ile-Ser-Arg-Lys-Ala-Lys-Gly
SEQ ID No12
HPDKWTVQPIVLPEKDSWTVNDIQKLVGKLNWASQ
His-Pro-Asp-Lys-Trp-Thr-Val-Gln-Pro-Ile-Val-Leu-Pro-Glu-Lys-Asp-Ser-Trp-Thr-Val-Asn-Asp-Ile-Gln-Lys-Leu-Val-Gly-Lys-Leu-Asn-Trp-Ala-Ser-Gln
SEQ ID No13
PAIFQSSMTKILEPFRKQNPDIVIYQYMDDLYVGS
Pro-Ala-Ile-Phe-Gln-Ser-Ser-Met-Thr-Lys-Ile-Leu-Glu-Pro-Phe-Arg-Lys-Gln-Asn-Pro-Asp-Ile-Val-Ile-Tyr-Gln-Tyr-Met-Asp-Asp-Leu-Tyr-Val-Gly-Ser
SEQ ID No14
MRGAHTNDVKQLTEAVQKIATESIVIWGKTPKFKL
Met-Arg-Gly-Ala-His-Thr-Asn-Asp-Val-Lys-Gln-Leu-Thr-Glu-Ala-Val-Gln-Lys-Ile-Ala-Thr-Glu-Ser-Ile-Val-Ile-Trp-Gly-Lys-Thr-Pro-Lys-Phe-Lys-Leu
SEQ ID No15
EKAFSPEVIPMFSALSEGATPQDLNTMLNTVGGHQ
Glu-Lys-Ala-Phe-Ser-Pro-Glu-Val-Ile-Pro-Met-Phe-Ser-Ala-Leu-Ser-Glu-Gly-Ala-Thr-Pro-Gln-Asp-Leu-Asn-Thr-Met-Leu-Asn-Thr-Val-Gly-Gly-His-Gln
SEQ ID No16
NLLRAIEAQQHLLQLTVWGIKQLQARVLAVERYLK
Asn-Leu-Leu-Arg-Ala-Ile-Glu-Ala-Gln-Gln-His-Leu-Leu-Gln-Leu-Thr-Val-Trp-Gly-Ile-Lys-Gln-Leu-Gln-Ala-Arg-Val-Leu-Ala-Val-Glu-Arg-Tyr-Leu-Lys
SEQ ID No17
ASVLSGGELDRWEKIRLRPGGKKKYKLKHIVWASR
Ala-Ser-Val-Leu-Ser-Gly-Gly-Glu-Leu-Asp-Arg-Trp-Glu-Lys-Ile-Arg-Leu-Arg-Pro-Gly-Gly-Lys-Lys-Lys-Tyr-Lys-Leu-Lys-His-Ile-Val-Trp-Ala-Ser-Arg
SEQ ID No18
ELYKYKVVKIEPLGVAPTKAKRRVVQREKRAVGIG
Glu-Leu-Tyr-Lys-Tyr-Lys-Val-Val-Lys-Ile-Glu-Pro-Leu-Gly-Val-Ala-Pro-Thr-Lys-Ala-Lys-Arg-Arg-Val-Val-Gln-Arg-Glu-Lys-Arg-Ala-Val-Gly-Ile-Gly
SEQ ID No19
FPISPIETVPVKLKPGMDGPKVKQWPLTEEKIKAL
Phe-Pro-Ile-Ser-Pro-Ile-Glu-Thr-Val-Pro-Val-Lys-Leu-Lys-Pro-Gly-Met-Asp-Gly-Pro-Lys-Val-Lys-Gln-Trp-Pro-Leu-Thr-Glu-Glu-Lys-Ile-Lys-Ala-Leu
SEQ ID No20
QIYQEPFKNLKTGKYARMRGAHTNDVKQLTEAVQK
Gln-Ile-Tyr-Gln-Glu-Pro-Phe-Lys-Asn-Leu-Lys-Thr-Gly-Lys-Tyr-Ala-Arg-Met-Arg-Gly-Ala-His-Thr-Asn-Asp-Val-Lys-Gln-Leu-Thr-Glu-Ala-Val-Gln-Lys
SEQ ID No21
NLLRAIEAQQHLLQLTVWGIKQLQARVLAVERYLK
Asn-Leu-Leu-Arg-Ala-Ile-Glu-Ala-Gln-Gln-His-Leu-Leu-Gln-Leu-Thr-Val-Trp-Gly-Ile-Lys-Gln-Leu-Gln-Ala-Arg-Val-Leu-Ala-Val-Glu-Arg-Tyr-Leu-Lys
SEQ ID No22
AGLKKKKSVTVLDVGDAYFSVPLDKDFRKYTAFTI
Ala-Gly-Leu-Lys-Lys-Lys-Lys-Ser-Val-Thr-Val-Leu-Asp-Val-Gly-Asp-Ala-Tyr-Phe-Ser-Val-Pro-Leu-Asp-Lys-Asp-Phe-Arg-Lys-Tyr-Thr-Ala-Phe-Thr-Ile
SEQ ID No23
TTNQKTELQAIHLALQDSGLEVNIVTDSQYALGII
Thr-Thr-Asn-Gln-Lys-Thr-Glu-Leu-Gln-Ala-Ile-His-Leu-Ala-Leu-Gln-Asp-Ser-Gly-Leu-Glu-Val-Asn-Ile-Val-Thr-Asp-Ser-Gln-Tyr-Ala-Leu-Gly-Ile-Ile
SEQ ID No24
VSQNYPIVQNLQGQMVHQAISPRTLNAWVKVVEEK
Val-Ser-Gln-Asn-Tyr-Pro-Ile-Val-Gln-Asn-Leu-Gln-Gly-Gln-Met-Val-His-Gln-Ala-Ile-Ser-Pro-Arg-Thr-Leu-Asn-Ala-Trp-Val-Lys-Val-Val-Glu-Glu-Lys
SEQ ID No25
EAELELAENREILKEPVHGVYYDPSKDLIAEIQKQ
Glu-Ala-Glu-Leu-Glu-Leu-Ala-Glu-Asn-Arg-Glu-Ile-Leu-Lys-Glu-Pro-Val-His-Gly-Val-Tyr-Tyr-Asp-Pro-Ser-Lys-Asp-Leu-Ile-Ala-Glu-Ile-Gln-Lys-Gln
SEQ ID No26
TPDKKHQKEPPFLWMGYELHPDKWTVQPIVLPEKD
Thr-Pro-Asp-Lys-Lys-His-Gln-Lys-Glu-Pro-Pro-Phe-Leu-Trp-Met-Gly-Tyr-Glu-Leu-His-Pro-Asp-Lys-Trp-Thr-Val-Gln-Pro-Ile-Val-Leu-Pro-Glu-Lys-Asp
SEQ ID No27
EPFRDYVDRFYKTLRAEQASQEVKNWMTETLLVQN
Glu-Pro-Phe-Arg-Asp-Tyr-Val-Asp-Arg-Phe-Tyr-Lys-Thr-Leu-Arg-Ala-Glu-Gln-Ala-Ser-Gln-Glu-Val-Lys-Asn-Trp-Met-Thr-Glu-Thr-Leu-Leu-Val-Gln-Asn
SEQ ID No28
NEWTLELLEELKSEAVRHFPRIWLHGLGQHIYETY
Asn-Glu-Trp-Thr-Leu-Glu-Leu-Leu-Glu-Glu-Leu-Lys-Ser-Glu-Ala-Val-Arg-His-Phe-Pro-Arg-Ile-Trp-Leu-His-Gly-Leu-Gly-Gln-His-Ile-Tyr-Glu-Thr-Tyr
SEQ ID No29
EGLIYSQKRQDILDLWVYHTQGYFPDWQNYTPGPG
Glu-Gly-Leu-Ile-Tyr-Ser-Gln-Lys-Arg-Gln-Asp-Ile-Leu-Asp-Leu-Trp-Val-Tyr-His-Thr-Gln-Gly-Tyr-Phe-Pro-Asp-Trp-Gln-Asn-Tyr-Thr-Pro-Gly-Pro-Gly
SEQ ID No30
HFLKEKGGLEGLIYSQKRQDILDLWVYHTQGYFPD
His-Phe-Leu-Lys-Glu-Lys-Gly-Gly-Leu-Glu-Gly-Leu-Ile-Tyr-Ser-Gln-Lys-Arg-Gln-Asp-Ile-Leu-Asp-Leu-Trp-Val-Tyr-His-Thr-Gln-Gly-Tyr-Phe-Pro-Asp
SEQ ID No3l
FPVRPQVPLRPMTYKAAVDLSHFLKEKGGLEGLIY
Phe-Pro-Val-Arg-Pro-Gln-Val-Pro-Leu-Arg-Pro-Met-Thr-Tyr-Lys-Ala-Ala-Val-Asp-Leu-Ser-His-Phe-Leu-Lys-Glu-Lys-Gly-Gly-Leu-Glu-Gly-Leu-Ile-Tyr
SEQ ID No32
FPQITLWQRPLVTIKIGGQLKEALLDTGADDTVLE
Phe-Pro-Gln-Ile-Thr-Leu-Trp-Gln-Arg-Pro-Leu-Val-Thr-Ile-Lys-Ile-Gly-Gly-Gln-Leu-Lys-Glu-Ala-Leu-Leu-Asp-Thr-Gly-Ala-Asp-Asp-Thr-Val-Leu-Glu
SEQ ID No33
LVITTYWGLHTGERDWHLGQGVSIEWRKKRYSTQV
Leu-Val-Ile-Thr-Thr-Tyr-Trp-Gly-Leu-His-Thr-Gly-Glu-Arg-Asp-Trp-His-Leu-Gly-Gln-Gly-Val-Ser-Ile-Glu-Trp-Arg-Lys-Lys-Arg-Tyr-Ser-Thr-Gln-Val
SEQ ID No34
APPEESFRFGEETTTPSQKQEPIDKELYPLASLRS
Ala-Pro-Pro-Glu-Glu-Ser-Phe-Arg-Phe-Gly-Glu-Glu-Thr-Thr-Thr-Pro-Ser-Gln-Lys-Gln-Glu-Pro-Ile-Asp-Lys-Glu-Leu-Tyr-Pro-Leu-Ala-Ser-Leu-Arg-Ser
SEQ ID No35
KRRVVQREKRAVGIGAMFLGFLGAAGSTMGAASMT
Lys-Arg-Arg-Val-Val-Gln-Arg-Glu-Lys-Arg-Ala-Val-Gly-Ile-Gly-Ala-Met-Phe-Leu-Gly-Phe-Leu-Gly-Ala-Ala-Gly-Ser-Thr-Met-Gly-Ala-Ala-Ser-Met-Thr
SEQ ID No36
GLGQHIYETYGDTWAGVEAIIRILQQLLFIHFRIG
Gly-Leu-Gly-Gln-His-Ile-Tyr-Glu-Thr-Tyr-Gly-Asp-Thr-Trp-Ala-Gly-Val-Glu-Ala-Ile-Ile-Arg-Ile-Leu-Gln-Gln-Leu-Leu-Phe-Ile-His-Phe-Arg-Ile-Gly
用于包括进用于HIV预防或治疗的疫苗的候选肽可以是来自以任何这样组合的结构或功能区Gag、Pol、Nef、Env、Vif、Vpr、Vpu、Tat或Rev的任何的肽。
Claims (32)
1.一种CmFn-CyHx-L结构或其衍生物的碳氟化合物载体,其中m=3到30,n<=2m+1,y=0到15,x<=2y,(m+y)=3-30以及L是有助于共价连接到抗原的配基。
2.一种CmFn-CyHx-(Sp)-R结构或其衍生物的碳氟化合物载体-抗原构建物,其中m=3到30,n<=2m+1,y=0到15,x<=2y,(m+y)=3-30并且其中Sp是可选择的化学间隔物部分以及R是抗原。
4.根据权利要求2所述的碳氟化合物载体-抗原构建物,其结构为
其中Sp是可选择的化学间隔物部分以及R是抗原。
6.根据权利要求2至5任一所述的碳氟化合物载体-抗原构建物,其中R是来自病毒、细菌、寄生虫、自体蛋白质或癌症抗原的抗原。
7.根据权利要求2至6任一所述的碳氟化合物载体-抗原构建物,其中R是蛋白质、蛋白质亚基、肽、碳水化合物或脂或其组合。
8.根据权利要求2至5任一所述的碳氟化合物载体-抗原构建物,其中R包括来自病毒蛋白质的一种或多种表位。
9.根据权利要求2至5任一所述的碳氟化合物载体-抗原构建物,其中R包括来自人类免疫缺陷型病毒蛋白质的一种或多种表位。
10.根据权利要求2至5任一所述的构建物,其中R是由7至70个氨基酸组成的肽。
11.根据权利要求2至5任一所述的构建物,其中R包括至少一种I类MHC或II类MHC细胞表位、或B细胞表位。
12.根据权利要求2至5任一所述的构建物,其中R包括两种以上或更多种的重叠表位。
13.根据权利要求2至5任一所述的碳氟化合物载体-抗原构建物,其中R是HIV表位。
14.根据权利要求2至5任一所述的碳氟化合物载体-抗原构建物,其中R是肽,其选自2004 Los Alamos National Laboratory数据库或其片段、衍生物、类似物或其组合。
15.根据权利要求2至5任一所述的碳氟化合物载体-抗原构建物,其中R是肽,其选自SEQ ID No 1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35或36,或其片段、衍生物、类似物或其组合。
16.根据权利要求2至5任一所述的碳氟化合物载体-抗原构建物,其中R是一种或多种HIV env表位。
17.根据权利要求13所述的碳氟化合物载体-抗原构建物,其中R是HIV env表位肽,其具有氨基酸序列NNTRKRIRIQRGPGRAFVTIGK-NH2。
18.根据权利要求1所述的碳氟化合物载体,其非共价地与抗原联合。
19.根据权利要求2至5任一所述的碳氟化合物载体-抗原构建物,其中R包括多重表位和/或融合肽。
20.一种预防或治疗的制剂,其包括根据权利要求2-19所述的一种或多种碳氟化合物载体-抗原构建物,可选择地与一种或多种药学上可接受传递体、赋形剂、稀释剂或佐剂组合。
21.根据权利要求20所述的预防或治疗的制剂,其配制成用于胃肠外的、口腔的、眼睛的、直肠的、鼻的、经皮肤的、局部的或阴道的给药。
22.根据权利要求20所述的预防或治疗的制剂,其是液体、固体、气溶胶或气体。
23.根据权利要求20-22任一所述的预防或治疗的制剂,其包括佐剂,所述佐剂选自由胞壁酰二肽(MDP)衍生物、CpG、单磷酰类脂A、水包油佐剂、油包水佐剂、铝盐、免疫刺激复合物(immunostimulating complex)(ISCOMs)、脂质体、微粒(microparticule)、皂甙、细胞因子、或细菌毒素和类毒素组成的组。
24.根据权利要求2-19任一所述碳氟化合物载体-抗原构建物或根据权利要求20至23任一所述制剂的用途,其用于预防性疫苗或免疫疗法的药物产品的制备。
25.根据权利要求1所述的碳氟化合物载体的用途,其用于根据权利要求2至19任一所述的碳氟化合物载体-抗原构建物的制备。
26.根据权利要求24所述的用途,其中所述疫苗或产品是用于胃肠外的、粘膜的、口腔的、鼻的、局部的、眼睛的、直肠的、经皮肤的、或阴道的给药。
27.一种治疗或免疫需要其的主体的方法,其包括给药有效量的根据权利要求2至19任一所述的构建物或根据权利要求20至23任一所述的制剂的步骤。
28.一种在需要其的主体中刺激免疫应答的方法,其包括给药有效量的根据权利要求2至19任一所述的构建物或根据权利要求20至23任一所述的制剂的步骤。
29.根据权利要求28所述的方法,其中所述主体是哺乳动物、优选地是人类。
30.根据权利要求27-29任一所述的方法,其中所述构建物或制剂与抗病毒疗法结合。
31.根据权利要求27-29任一所述的方法,其中所述构建物或制剂是用高效抗反转录病毒疗法(HAART)给药的。
32.根据权利要求1所述的碳氟化合物载体或根据权利要求2至19任一所述的碳氟化合物载体-抗原构建物的用途,其用于医学、药物。
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CN105148265A (zh) * | 2010-12-31 | 2015-12-16 | 英国瓦克辛公司 | 碳氟连接的肽制剂 |
CN105148265B (zh) * | 2010-12-31 | 2018-09-21 | 英国阿尔特免疫公司 | 碳氟连接的肽制剂 |
CN105555311A (zh) * | 2013-07-23 | 2016-05-04 | 诺瓦利克有限责任公司 | 稳定的抗体组合物 |
CN105555311B (zh) * | 2013-07-23 | 2021-10-08 | 诺瓦利克有限责任公司 | 稳定的抗体组合物 |
CN112638410A (zh) * | 2018-04-04 | 2021-04-09 | 艾尔特免疫公司 | 诱导t细胞的疫苗组合物组合及其用途 |
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